Imidazo[1,3,5]triazinones and their use

ABSTRACT

The invention relates to imidazo[1,3,5]triazinones, a method for their production and methods of use, in particular as inhibitors of cyclic GMP metabolizing phosphodiesterases.

This application is a continuation of U.S. patent application Ser. No.10/168,194, filed on Nov. 4, 2002, now U.S. Pat. No. 6,803,365; which isa 371 application of PCT/EP00/12597, filed Dec. 12, 2000.

The present invention relates to novel imidazo[1,3,5]triazinones, toprocesses for preparing them and to their use as medicaments, inparticular as inhibitors of cGMP-metabolizing phosphodiesterases.

The synthesis of imidazo[1,3,5]triazinones is described in J. Org. Chem.(1979), 44(10), 1740–2; in J. Org. Chem. (1979), 44(22), 3835–9; in J.Org. Chem. (1981),46 (18), 3681–5 and J. Chem. Res. Synop. (1994), (3),96–7. These publications did not report any biological effect.

Imidazo[1,3,5]triazinones which possess antiviral and/or antitumoreffect are described in Nucleosides Nucleotides (1987), 6(4), 663–78; inEur. J. Med. Chem. (1992), 27(3), 259–66; in J. Heterocycl. Chem.(1993), 30(5), 1341–9; in J. Med. Chem. (1995), 38(18), 3558–68 andBiorg. Med. Chem. Lett. (1996), 6(2), 185–8. The compounds which arementioned in these literature references were for the most part preparedas guanine or guanosine analogs and are therefore as a rule substitutedin the 2 position by —NH₂, —SH or —H. None of the compounds which aredescribed contains a phenyl ring or a substituted phenyl ring in the 2position. None of the compounds which are described has been reported tohave an inhibitory effect on phosphodiesterases.

The compounds according to the invention are potent inhibitors of cyclicguanosine 3′,5′-monophophate-metabolizing phosphodiesterases(cGMP-PDEs). In accordance with the nomenclature of Beavo and Reifsnyder(Trends in Pharmacol. Sci. 11, 150–155, 1990), these phosphodiesterasesare the phosphodiesterase isoenzymes PDE-I, PDE-II and PDE-V.

An increase in the concentration of cGMP can lead to therapeutic,antiaggregatory, antithrombotic, antiproliferative, antivasospastic,vasodilatory, natriuretic and diuretic effects. It can exert an effecton the short-term or long-term modulation of vascular and cardiacinotropy, cardiac rhythm and stimulus conduction in the heart (J. C.Stoclet, T. Keravis, N. Komas and C. Kugnier, Exp. Opin. Invest. Drugs(1995), 4 (11), 1081–1100). Inhibition of the cGMP-PDEs can alsostrengthen erection. These compounds are therefore suitable for treatingerectile dysfunction.

The present invention now relates to novel imidazo[1,3,5]triazinones ofthe general formula (I)

in which

-   R¹ represents straight-chain or branched alkyl having up to 4 carbon    atoms,-   R² represents straight-chain or branched alkyl having up to 4 carbon    atoms or represents (C₃–C₈)-cycloalkyl,-   R³ represents hydrogen or straight-chain or branched alkyl having up    to 4 carbon atoms,-   R⁴ and R⁵ are identical or different and represent hydrogen,    (C₁–C₆)-alkoxy or hydroxyl or represent (C₁–C₈)-alkyl which is    optionally substituted, up to 3 times, identically or differently,    by hydroxyl or (C₁–C₆)-alkoxy or by radicals of the formulae

-   -   in which    -   R⁶ and R⁷ are identical or different and denote hydrogen or        (C₁–C₆)-alkyl,    -   and/or, for its part, (C₁–C₈)-alkyl is optionally substituted by        phenyl or phenoxy which, for their part, are optionally        substituted, once to three times, identically or differently, by        halogen, hydroxyl, (C₁–C₆)-alkoxy or (C₁–C₆)-alkyl or by a        radical of the formula —SO₂NR⁸R⁹,    -   in which    -   R⁸ and R⁹ are identical or different and denote hydrogen or        (C₁–C₆)-alkyl,        or

-   R⁴ represents hydrogen or methyl,    and

-   R⁵ represents radicals of the formulae

-   -   or    -   represents phenyl which is optionally substituted, up to 3        times, identically or differently, by halogen, acetyl or        (C₁–C₆)-alkoxy or by radicals of the formulae

—NR¹⁰R¹¹ or —CH₂—P(O)(OR¹²)(OR¹³),

-   -   in which    -   R¹⁰ and R¹¹ are identical or different and denote hydrogen or        (C₁–C₄)-alkyl,    -   R¹² and R¹³ are identical or different and denote hydrogen or        (C₁–C₆)-alkyl,        or

-   R⁴ and R⁵, together with the nitrogen atom to which they are bonded,    form radicals of the formulae

-   -   in which    -   R¹⁴ and R¹⁵ are identical or different and denote hydroxyl,        hydrogen or (C₁–C₄)-alkyl which is optionally substituted by        hydroxyl,    -   or    -   R¹⁴ denotes hydrogen,    -   and    -   R¹⁵ denotes a radical of the formula

-   -   or    -   R¹⁴ and R¹⁵ together form a radical of the formula ═N—O—CH₃,    -   R¹⁶ denotes hydrogen or (C₁–C₆)-alkyl which is optionally        substituted by hydroxyl, or denotes        -   a 5- to 6-membered, aromatic heterocycle having up to 3            heteroatoms from the series S, N and/or O,            and the salts, N-oxides and isomeric forms thereof.

The compounds according to the invention can exist in stereoisomericforms which either relate to each other as image and mirror image(enantiomers) or which do not relate to each other as image and mirrorimage (diastereomers). The invention relates to both the enantiomers ordiastereomers or their respective mixtures. The racemic forms, as wellas the diastereomers, can be separated into the stereoisomericallyuniform constituents in a known manner.

The substances according to the invention can also be present as salts.Within the context of the invention, preference is given tophysiologically harmless salts.

Physiologically harmless salts can be salts of the compounds accordingto the invention with inorganic or organic acids. Preference is given tosalts with inorganic acids, such as hydrochloric acid, hydrobromic acid,phosphoric acid or sulfuric acid, or salts with organic carboxylic orsulfonic acid, such as acetic acid, maleic acid, fumaric acid, malicacid, citric acid, tartaric acid, lactic acid or benzoic acid, ormethanesulfonic acid, ethanesulfonic acid, phenylsulfonic acid,toluenesulfonic acid or naphthalenedisulfonic acid.

Physiologically harmless salts can equally well be metal or ammoniumsalts of the compounds according to the invention. Particular preferenceis given, for example, to sodium, potassium, magnesium or calcium salts,and also to ammonium salts which are derived from ammonia, or to organicamines, such as ethylamine, di- or triethylamine, di- ortriethanolamine, dicyclohexylamine, dimethylaminoethanol, arginine,lysine, ethylenediamine or 2-phenylethylamine.

(C₃–C₈)-Cycloalkyl represents cyclopropyl, cyclopentyl, cyclobutyl,cyclohexyl, cycloheptyl or cyclooctyl. Those which may be mentioned asbeing preferred are: cyclopropyl, cyclopentyl and cyclohexyl.

(C₁–C₈)-Alkyl (C₁–C₆)-alkyl and (C₁–C₄)-alkyl represents astraight-chain or branched alkyl radical having from 1 to 8, from 1 to 6and from 1 to 4 carbon atoms, respectively. Those which may be mentionedby way of example are: methyl, ethyl, n-propyl, isopropyl, n-butyl,isobutyl, tert-butyl, n-pentyl and n-hexyl. Preference is given to astraight-chain or branched alkyl radical having from 1 to 4 carbonatoms. Particular preference is given to a straight-chain or branchedalkyl radical having from 1 to 3 carbon atoms.

(C₁–C₆)-Alkoxy represents a straight-chain or branched alkoxy radicalhaving from 1 to 6 carbon atoms. Those which may be mentioned by way ofexample are: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, tert-butoxy, n-pentoxy and n-hexoxy. Preference is given to astraight-chain or branched alkoxy radical having from 1 to 4 carbonatoms. Particular preference is given to a straight-chain or branchedalkoxy radical having from 1 to 3 carbon atoms.

Halogen generally represents fluorine, chlorine, bromine and iodine.Preference is given to fluorine, chlorine and bromine. Particularpreference is given to fluorine and chlorine.

A 5- to 6-membered aromatic heterocycle having up to 3 heteroatoms fromthe series S, O and/or N represents, for example, pyridyl, pyrimidyl,pyridazinyl, thienyl, furyl, pyrrolyl, thiazolyl, oxazolyl orimidazolyl. Preference is given to pyridyl, pyrimidyl, pyridazinyl,furyl and thienyl.

Preference is given to compounds according to the invention of thegeneral formula (I),

in which

-   R¹ represents methyl or ethyl,-   R² represents straight-chain or branched alkyl having up to 3 carbon    atoms or represents (C₃–C₆)-cycloalkyl,-   R³ represents straight-chain or branched alkyl having up to 3 carbon    atoms,-   R⁴ and R⁵ are identical or different and represent hydrogen,    (C₁–C₄)-alkoxy or hydroxyl or represent (C₁–C₇)-alkyl which is    optionally substituted, up to 3 times, identically or differently,    by hydroxyl or (C₁–C₄)-alkoxy or by radicals of the formulae

-   -   in which    -   R⁶ and R⁷ are identical or different and denote hydrogen or        methyl,    -   and/or, for its part, (C₁–C₇)-alkyl is optionally substituted by        phenyl or phenoxy which, for their part, are optionally        substituted, once to three times, identically or differently, by        fluorine, chlorine, hydroxyl, (C₁–C₄)-alkoxy or (C₁–C₄)-alkyl or        by a radical of the formula —SO₂NH₂,        or

-   R⁴ represents hydrogen or methyl,    and

-   R⁵ represents radicals of the formulae

-   -   or    -   represents phenyl which is optionally substituted, up to 3        times, identically or differently, by fluorine, chlorine, acetyl        or (C₁–C₄)-alkoxy or by radicals of the formulae

—NR¹⁰R¹¹ or —CH₂—P(O)(OR¹²)(OR¹³),

-   -   in which    -   R¹⁰ and R¹¹ are identical or different and denote hydrogen or        methyl,    -   R¹² and R¹³ are identical or different and denote hydrogen or        methyl,        or

-   R⁴ and R⁵, together with the nitrogen atom to which they are bonded,    form radicals of the formulae

-   -   in which    -   R¹⁴ and R¹⁵ are identical or different and denote hydroxyl,        hydrogen or (C₁–C₃)-alkyl which is optionally substituted by        hydroxyl,    -   or    -   R¹⁴ denotes hydrogen,    -   and    -   R¹⁵ denotes a radical of the formula

-   -   or    -   R¹⁴ and R¹⁵ together form a radical of the formula ═N—O—CH₃,    -   R¹⁶ denotes hydrogen or (C₁–C₅)-alkyl which is optionally        substituted by hydroxyl, or denotes pyridyl, pyrimidyl, furyl,        pyrryl or thienyl,        and the salts, N-oxides and isomeric forms thereof.

Particular preference is given to compounds according to the inventionof the general formula (I),

in which

-   R¹ represents methyl or ethyl,-   R² represents n-propyl or represents cyclopentyl,-   R³ represents methyl, ethyl or n-propyl,-   R⁴ and R⁵ are identical or different and represent hydrogen,    (C₁–C₃)-alkoxy or hydroxyl or represent (C₁–C₆)-alkyl which is    optionally substituted, up to 3 times, identically or differently,    by hydroxyl or (C₁–C₃)-alkoxy or by radicals of the formulae

-   -   in which    -   R⁶ and R⁷ are identical or different and denote hydrogen or        methyl, and/or, for its part, (C₁–C₆)-alkyl is optionally        substituted by phenyl or phenoxy which, for their part, are        optionally substituted, once to three times, identically or        differently, by fluorine, hydroxyl or methoxy or by a radical of        the formula —SO₂NH₂,        or

-   R⁴ represents hydrogen or methyl,    and

-   R⁵ represents radicals of the formulae

-   -   or    -   represents phenyl which is optionally substituted, up to 3        times, identically or differently, by fluorine, acetyl or        methoxy or by radicals of the formulae

-   -   in which    -   R¹⁰ and R¹¹ are identical or different and denote hydrogen or        methyl,    -   R¹² and R¹³ denote methyl,        or

-   R⁴ and R⁵, together with the nitrogen atom to which they are bonded,    form radicals of the formulae

-   -   in which    -   R¹⁴ and R¹⁵ are identical or different and denote hydroxyl,        hydrogen or a radical of the formula —(CH₂)₂—OH,    -   or    -   R¹⁴ denotes hydrogen    -   and    -   R¹⁵ denotes a radical of the formula

-   -   or    -   R¹⁴ and R¹⁵ together form a radical of the formula ═N—O—CH₃,    -   R¹⁶ denotes hydrogen, pyrimidyl or a radical of the formula        —(CH₂)₂—OH,        and the salts, N-oxides and isomeric forms thereof.

Very particular preference is given to the following compounds accordingto the invention:

Structure

In addition, a process was found for preparing the compounds accordingto the invention of the general formula (I), in which process compoundsof the general formula (II)

in which

-   R¹, R² and R³ have the abovementioned meaning,    are first of all converted, by reaction with chlorosulfonic acid    (ClSO₃H), where appropriate in inert solvents, where appropriate in    the presence of a base, into the compounds of the general formula    (III)

in which

-   R¹, R² and R³ have the abovementioned meaning,    and, in a last step, are reacted with amines of the general formula    (IV)    HN—R⁴R⁵  (IV),    in which-   R⁴ and R⁵ have the abovementioned meaning.

The process according to the invention can be explained, by way ofexample, by the following formula scheme:

Solvents which are suitable for the individual steps are the customaryorganic solvents which are not altered under the reaction conditions.These solvents preferably include ethers, such as diethyl ether,dioxane, tetrahydrofuran or glycol dimethyl ether, or hydrocarbons, suchas benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions,or halogenohydrocarbons, such as dichloromethane, trichloromethane,tetrachloromethane, dichloroethane, trichloroethylene or chlorobenzene,or ethyl acetate, dimethylformamide, hexamethylphosphoric triamide,acetonitrile, acetone, dimethoxyethane or pyridine. It is likewisepossible to use mixtures of the abovementioned solvents.

In general, the reaction temperatures can vary over a relatively widerange. In general, the temperatures employed are in a range of from −20°C. to 200° C., preferably of from 0° C. to 70° C.

In general, the process steps according to the invention are carried outunder standard pressure. However, it is also possible to carry them outunder positive pressure or under negative pressure (e.g. in a range from0.5 to 5 bar).

The reactions can, for example, take place in a temperature range offrom 0° C. to room temperature and under standard pressure.

The compounds of the general formula (II) are novel and can be preparedby reacting compounds of the general formula (V)

in which

-   R¹ has the abovementioned meaning,-   in the NaOC₂H₅/C₂H₅OH system, with compounds of the general formula    (VI)    R²-halogen  (VI),    in which-   R² has the abovementioned meaning,    to give the compounds of the general formula (VII)

in which

-   R¹ and R² have the abovementioned meaning,    and subsequently, likewise in the NaO₂H₅/C₂H₅OH system, carrying out    a reaction with compounds of the general formula (VIII)

in which

-   R³ has the abovementioned meaning,    to give the compounds of the general formula (IX)

in which

-   R¹, R² and R³ have the abovementioned meaning,    and finally cyclizing in inert solvents, in the presence of    hexamethyldisilazane (HMDS) and chlorotrimethylsilane (TMSCl).

Solvents which are suitable for the individual steps are the customaryorganic solvents which are not altered under the reaction conditions.These solvents preferably include ethers, such as diethyl ether,dioxane, tetrahydrofuran or glycol dimethyl ether, or hydrocarbons, suchas benzene, toluene, xylene, hexane, cyclohexane or petroleum fractions,or halogenohydrocarbons, such as dichloromethane, trichloromethane,tetrachloromethane, dichloroethane, trichloroethylene or chlorobenzene,or ethyl acetate, dimethylformamide, hexamethylphosphoric triamide,acetonitrile, acetone, dimethoxyethane or pyridine. It is likewisepossible to use mixtures of the abovementioned solvents.

In general, the reaction temperatures can vary within a relatively widerange. In general, the temperatures employed are in a range from −20° C.to 200° C., preferably of from 0° C. to 70° C.

The process steps according to the invention are generally carried outunder standard pressure. However it is also possible to carry them outunder positive pressure or under negative pressure (e.g. in a range from0.5 to 5 bar).

The reactions can, for example, take place in a temperature range offrom 0° C. to room temperature and under standard pressure.

The compounds of the general formula (III) are novel and can be preparedas described above.

The compounds of the general formulae (IV), (V), (VI), (VII) and (VIII)are either known per se or can be prepared using customary methods.

Some of the compounds of the general formula (IX) are novel and can beprepared using customary methods.

The compounds according to the invention of the general formula (I)exhibit a valuable pharmacological spectrum of activity which it was notpossible to foresee.

They inhibit either one or several of the c-GMP-metabolizingphosphodiesterases (PDE I, PDE II and PDE V). This leads to an increasein c-GMP. The differing expression of the phosphodiesterases indifferent cells, tissues and organs, as well as the differingsubcellular location of these enzymes, make it possible, in combinationwith the selective inhibitors according to the invention, to address thedifferent cGMP-regulated processes selectively.

In addition, the compounds according to the invention augment the effectof substances such as EDRF (endothelium-derived relaxing factor) and ANP(atrial natriuretic peptide), of nitro vasodilators and all othersubstances which increase the concentration of the cGMP in another waythan phosphodiesterase inhibitors.

The compounds according to the invention of the general formula (I) aretherefore suitable for the prophylaxis and/or treatment of diseases inwhich an increase in the concentration of cGMP is therapeutic, i.e.diseases which are connected with cGMP-regulated processes (in English,usually simply termed cGMP-related diseases). These diseases includecardiovascular diseases, diseases of the urogenital system andcerebrovascular diseases.

Within the meaning of the present invention, the term “cardiovasculardiseases” covers diseases such as high blood pressure, neuronalhypertension, stable and unstable angina, peripheral and cardiacvascular diseases, arrhythmias, thromboembolic diseases and ischemiassuch as myocardial infarction, stroke, transistory and ischemic attacks,angina pectoris and peripheral circulatory disturbances, and alsoprevention of restenoses following thrombolysis therapy, percutaneoustransluminal angioplasty (PTA), percutaneous transluminal coronaryangioplasties (PTCA) and bypass.

Furthermore, the compounds according to the invention of the generalformula (I) can also have importance for cerebrovascular diseases. Theseinclude, for example, cerebral ischemia, stroke, reperfusion damage,brain trauma, edemas, cerebral thromboses, dementia and Alzheimer'sdisease.

The relaxing effect on smooth musculature makes them suitable fortreating disorders of the urogenital system such as prostate hypertrophyand incontinence and also, in particular, for treating erectiledysfunction and female sexual dysfunction.

Activity of the Phosphordiesterases (PDEs)

The cGMP-stimulatable PDE II, the cGMP-inhibitable PDE III and thecAMP-specific PDE IV were isolated either from porcine heart myocardiumor from bovine heart myocardium. The Ca²⁺-calmodulin-stimulatable PDE Iwas isolated from porcine aorta, porcine brain or, preferably, frombovine aorta. The c-GMP-specific PDE V was obtained from porcine smallintestine, porcine aorta, human blood platelets and, preferably, frombovine aorta. Purification was effected by means of anion exchangechromatography on Pharmacia MonoQ^(R), essentially in accordance withthe method described by M. Hoey and Miles D. Houslay, BiochemicalPharmacology, Vol. 40, 193–202 (1990) and C. Lugman et al. BiochemicalPharmacology Vol. 35 1743–1751 (1986).

The enzyme activity is determined in a 100 μl test mixture, in 20 mMTris/HCl buffer pH 7.5, which contains 5 mM MgCl₂, 0.1 mg of bovineserum albumin/ml and either 800 Bq of ³HcAMP or ³HcGMP. The finalconcentration of the corresponding nucleotides is 10⁻⁶ mol/l. Thereaction is started by adding the enzyme, with the quantity of enzymebeing measured such that approx. 50% of the substrate is transformedduring the incubation time of 30 min. In order to test thecGMP-stimulatable PDE II, ³HcAMP is used as the substrate and 10⁻⁶ molof unlabeled cGMP/l is added to the mixture. In order to test theCa²⁺-calmodulin-dependent PDE I, 1 μM CaCl₂ and 0.1 μM calmodulin areadditionally added to the reaction mixture. The reaction is stopped byadding 100 μl of acetonitrile which contains 1 mM cAMP and 1 mM AMP. 100μl of the reaction mixture are separated by HPLC and the cleavageproducts are determined quantitatively online using a flow-throughscintillation counter. The substance concentration at which the reactionrate is decreased by 50% is measured. The “phosphodiesterase [³H]cAMP-SPA enzyme assay” and the “phosphodiesterase [³H] cGMP-SPA enzymeassay”, supplied by Amersham Life Science, were additionally used fortesting. The test was carried out using the experimental protocolspecified by the manufacturer. The [3H] cAMP-SPA assay was used fordetermining the activity of PDE II, with 10⁻⁶ M cGMP being added to thereaction mixture for the purpose of activating the enzyme. 10⁻⁷ Mcalmodulin and 1 μM CaCl₂ were added to the reaction mixture for thepurpose of measuring PDE I. PDE V was measured using the [³H] cGMP-SPAassay.

In principle, the inhibition of one or more phosphodiesterases of thistype leads to an increase in the concentration of cGMP. As a result, thecompounds are of interest for all therapies in which an increase in theconcentration of cGMP can be assumed to be therapeutic.

The investigation of the cardiovascular effects was carried out onnormotensive rats and on SH rats and on dogs. The substances wereadministered intravenously or orally.

The examination for erection-inducing effects was carried out onconscious rabbits [H. Naganuma, T. Egashira, J. Fuji, Clinical andExperimental Pharmacology and Physiology 20, 177–183 (1993)]. Thesubstances were administered orally or parenterally.

The novel active compounds, and also their physiologically harmlesssalts (e.g. hydrochlorides, maleates or lactates) can be converted, in aknown manner, into the customary formulations, such as tablets, coatedtablets, pills, granules, aerosols, syrups, emulsions, suspensions andsolutions, using inert, nontoxic, pharmaceutically suitable carriersubstances or solvents. In this connection, the therapeuticallyeffective compound should in each case be present at a concentration offrom about 0.5 to 90% by weight of the total mixture, i.e. in quantitieswhich are sufficient for achieving the specified dosage range.

The formulations are prepared, for example, by extending the activecompounds with solvents and/or carrier substances, where appropriateusing emulsifiers and/or dispersants, with it being possible, forexample when using water as a diluent, to use organic solvents asauxiliary solvents, where appropriate.

The administration is effected in a customary manner, preferably orally,transdermally or parenterally, for example perlingually, by the buccalroute, intravenously, nasally, rectally or by inhalation.

For use in humans, doses of from 0.001 to 50 mg/kg, preferably 0.01mg/kg–20 mg/kg, are generally administered when administering orally. Adose of 0.001 mg/kg–0.5 mg/kg is expedient when administeringparenterally, for example by way of mucosae, nasally, by the buccalroute or by inhalation.

Despite this, it can be necessary, where appropriate, to depart from theabove-mentioned quantities, specifically in dependence on the bodyweight or the nature of the route of administration, on the individualresponse to the medicament, on the nature of its formulation and on thetime or interval at which the administration takes place. Thus, it canin some cases be sufficient to make do with less than the abovementionedsmallest quantity whereas, in other cases, the abovementioned upperlimit has to be exceeded. When relatively large quantities are beingadministered, it may be advisable to divide up these quantities intoseveral individual doses which are given during the course of the day.

The compounds according to the invention are also suitable for use inveterinary medicine. For uses in veterinary medicine, the compounds, ortheir nontoxic salts, can be administered in a suitable formulation, inaccordance with common veterinary procedures. The veterinarian canestablish the nature of the application, and the dose, in accordancewith the nature of the animal to be treated.

In the following examples of preparing the precursors and end products,it is always necessary, in structural formulae containing one or moreunsaturated valences on the nitrogen atom or oxygen atom, to add ahydrogen.

In other words, in structures containing, for example, a structuralelement “—N—”, what is meant is actually “—NH—”, and in structurescontaining, for example, a structural element “—O”, what is meant isactually “—OH”.

Preparing the Precursors

EXAMPLE I

Ethyl 2-acetylamino-2-cyanopentanoate

1.35 g of sodium (58.8 mmol) are dissolved in 200 ml of ethanol and theresulting solution is cooled down to 0° C. 10 g (58.8 mmol) of ethylacetamidocyanoacetate are added. After a clear solution has formed, asolution of 7.23 g (58.8 mmol) of bromopropane in 10 ml of ethanol isadded dropwise and the reaction mixture is stirred at room temperaturefor 2 hours. A solution of 7.23 g (58.8 mmol) of bromopropane in 10 mlof ethanol is added once again and the reaction mixture is heated underreflux for 16 hours. The solvent is removed in vacuo and the residue istaken up in dichloromethane; the solution is washed with water and driedover magnesium sulfate. The solvent is removed in vacuo and the residueis stirred up with petroleum ether. After filtering off with suction,7.5 g (60%) of ethyl 2-acetylamino-2-cyanopentanoate are obtained.

200 MHz ¹H-NMR (CDCl₃): 1.00, t, 3H; 1.36, t, 3H; 1.51, m, 2H; 2.08, m,5H; 4.34, q, 2H; 6.45, s, broad, 1H.

EXAMPLE II

2-Ethoxy-benzonitrile

25 g (210 mmol) of 2-hydroxylbenzonitrile are heated, together with 87 gof potassium carbonate and 34.3 g (314.8 mmol) of ethyl bromide, in 500ml of acetone under reflux overnight. The solid is filtered off, thesolvent is removed in vacuo and the residue is distilled in vacuo. 30.0g (97%) of a colorless liquid are obtained.

200 MHz ¹H-NMR (DMSO-D₆): 1.48, t, 3H; 4.15, quart., 2H; 6.99, dt, 2H;7.51, dt, 2H.

EXAMPLE III

2-Ethoxy-benzamidine hydrochloride

21.4 g (400 mmol) of ammonium chloride are suspended in 375 ml oftoluene and the suspension is cooled down to 0° C. 200 ml of a 2 Msolution of trimethylaluminum in hexane are added dropwise and themixture is stirred at room temperature until the evolution of gas hascome to an end. After 29.44 g (200 mmol) of 2-ethoxybenzonitrile(example II) have been added, the reaction mixture is stirred overnightat 80° C. (bath).

Having been cooled down, the reaction mixture is added, while coolingwith ice, to a suspension consisting of 100 g of silica gel and 950 mlof chloroform and the mixture is stirred at room temperature for 30minutes. Filtration with suction is carried out and the subsequentwashing takes place with the same quantity of methanol. The motherliquor is evaporated and the resulting residue is stirred up with amixture of dichloromethane and methanol (9:1), after which the solid isfiltered off with suction and the mother liquor is evaporated. 3.4 g(76%) of a colorless solid are obtained.

200 MHz ¹H-NMR (DMSO-D₆): 1.36, t, 3H; 4.12, quart., 2H; 7.10, t, 1H;7.21, d, 1H; 7.52, m, 2H; 9.30, s, broad, 4H.

EXAMPLE IV

N-[6-Amino-2-(2-ethoxyphenyl)-4-oxo-5-propyl-4,5-dihydro-pyrimidin-5-yl]-acetamide

33 g of 2-ethoxybenzamidine hydrochloride (example III) are added to asolution of 3.97 g of sodium in 1300 ml of ethanol and the reactionmixture is stirred at room temperature for 45 minutes. The reactionmixture is filtered and the filtrate is added to a solution of 69.8 g(329 mmol) of ethyl 2-acetylamino-2-cyanopentanoate (example I) in 800ml of ethanol and the mixture is heated under reflux for 4 hours. Thesolvent is removed in vacuo and the residue is taken up indichloromethane; the organic phase is shaken with water and sodiumchloride solution and dried over sodium sulfate and the solvent isremoved in vacuo. Chromatographic purification(dichloromethane/methanol) yields 11.57 g (21%) ofN-[6-amino-2-(2-ethoxyphenyl)-4-oxo-5-propyl-4,5-dihydro-pyriminin-5-yl)-acetamide.

200 MHz ¹H-NMR (CDCl₃): 0.91, t, 3H; 1.41, m, 2H; 1.58, t, 3H; 2.07, m,5H; 4.39, q, 2H; 7.08, m, 3H; 7.53, dt, 1H; 8.41, dd, 1H.

EXAMPLE V

2-(2-Ethoxyphenyl)-6-methyl-8-propyl-3H-imidazo[1,5-a](1,3,5]triazin-4-one

11.41 g (105 mmol) of chlorotrimethylsilane are added to a solution of11.57 g (35 mmol) ofN-[6-amino-2-(2-ethoxyphenyl)-4-oxo-5-propyl-4,5-dihydro-pyriminin-5-yl]-acetamide(example IV) in 500 ml of pyridine and the reaction mixture is stirredat room temperature for 20 minutes. After 16.96 g (105 mmol) ofhexamethyldisilazane have been added, the reaction mixture is heatedunder reflux for 16 hours. The solvent is removed in vacuo and theresidue is taken up in dichloromethane; the solution is extracted withwater and 1 N HCl and dried over magnesium sulfate, after which thesolvent is removed in vacuo. The residue is stirred up with ether andthe solid residue is purified chromatographically (cyclohexane/ethylacetate). 1.655 g (15%) of solid are obtained.

200 MHz ¹H-NMR (CDCl₃): 1.02, t, 3H; 1.61, t, 3H; 1.80, hex, 2H; 2.80,t, 2H; 2.88, s, 3H, 4.30, q, 2H; 7.05, d, 1H; 7.15, t, 1H; 7.58, dt, 1H;8.39, dd, 1H; 10.35, s, broad, 1H.

EXAMPLE VI

4-Ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzenesulfonylchloride

1.64 g (5.25 mmol) of2-(2-ethoxyphenyl)-6-methyl-8-propyl-3H-imidazo[1,5-a][1,3,5]triazin-4-one(example VI) are added in portions to 3.14 ml of chlorosulfonic acidwhile cooling with ice. The reaction mixture is stirred at roomtemperature for 16 hours, then diluted with dichloromethane and pouredonto ice water. The organic phase is washed with water and dried overmagnesium sulfate and the solvent is removed in vacuo. 2.15 g (99%) of4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzene-sulfonylchloride are obtained.

200 MHz ¹H-NMR (CDCl₃): 0.92, t, 3H; 1.34, t, 3H; 1.71, hex, 2H; 2.80,t, 2H; 2.96, s, 3H; 4.15, q, 2H; 7.12, d, 1H; 7.73, dd, 1H; 7.81, d, 1H;12.5, s, broad, 1H.

EXAMPLE VII

Ethyl 2-acetylamino-2-cyano-2-cyclopentylethanoate

125 g of ethyl acetamidocyanoacetate (734.6 mmol) are added, at roomtemperature, to a solution of 17.74 g of sodium (771.3 mmol) in 1.2 l ofethanol. After a clear solution has been formed, 157.5 ml of cyclopentylbromide (1.47 mol) are added dropwise. The mixture is stirred overnightunder reflux and then concentrated on a rotary evaporator. The residueis taken up in dichloromethane and the solution is washed twice withwater, dried over magnesium sulfate and concentrated. The crystallineresidue is stirred up with ether and filtered off with suction.

Yield: 70.8 g (40.4% of theory)

MS (DCI, NH₃): m/z (%)=256 (M+H₂O) (100) ¹H-NMR (200 MHz, CDCl₃): δ=1.35(t, 3H); 1.55–1.82 (m, 7 H); 1.91–2.03 (m, 1 H); 2.06 (s, 3 H);2.37–2.50 (m, 1 H); 4.31 (q, 2 H); 6.79 (s, 1 H).

EXAMPLE VIII

N-[6-Amino-5-cyclopentyl-2-(2-ethoxyphenyl)-4-oxo-4,5-dihydropyrimidin-5-yl]acetamide

5.02 g (25 mmol) of 2-ethoxybenzamidine hydrochloride (example III) areadded to a solution of 0.6 g of sodium (26.25 mmol) in 80 ml of ethanol.After 45 min at room temperature, the resulting mixture is filtered intoa solution of 11.91 g (50 mmol) of ethyl2-acetylamino-2-cyano-2-cyclopentylethanoate in 120 ml of ethanol andthe mixture is subsequently stirred under reflux for 5 h. It is thenconcentrated and the residue is taken up in dichloromethane; thesolution is washed twice with water, dried and evaporated. The crudeproduct is purified by column chromatography on silica gel usingdichloromethane/methanol 9:1.

Yield 545.4 mg (6.1% of theory) MS (DCI, NH₃): m/z (%)=339 (M+H) (100)¹H-NMR (200 MHz, CDCl₃): δ=1.45–1.90 (m, 12 H); 2.05 (s, 3 H); 2.42–2.58(m, 1 H), 4.28 (q, 2 H); 6.99–7.14 (m, 2 H); 7.19 (s, 1 H); 7.53 (dt, 1H); 8.87 (dd, 1 H).

EXAMPLE IX

8-Cyclopentyl-2-(2-ethoxy-phenyl)-6-methyl-3H-imidazo[1,5-a][1,3,5]triazin-4-one

1,6 g (4.5 mmol) ofN-[6-amino-5-cyclopentyl-2-(2-ethoxyphenyl)-4-oxo-4,5-dihydropyrimidin-5-yl]acetamide(example VIII) are initially introduced in 64 ml of anhydrous pyridine.1.71 ml (13.5 mmol) of chlorotrimethylsilane are added dropwise and themixture is subsequently stirred at room temperature for 20 min. After2.8 ml (13.5 mmol) of hexamethyldisilazane have been added, the mixtureis subsequently stirred overnight under reflux. It is then evaporateddown to dryness and the residue is taken up in 80 ml of methanol; thesolution is stirred at room temperature for 45 min. It is thenevaporated and the residue is purified by flash chromatography usingcyclohexane/ethyl acetate 1:1.

Yield 727 mg (47.5% of theory) MS (DCI, NH₃): m/z (%)=339 (M+H) (100)¹H-NMR (200 MHz, CDCl₃ ): δ=1.60 (t, 3H); 1.65–2.12 (m, 8 H); 2.89 (s, 3H); 3.40 (qui, 1 H); 4.29 (q, 2 H); 7.0–7.18 (m, 2 H); 7.49 (dt, 1 H);8.48 (dd, 1 H); 10.31(bs, 1 H).

EXAMPLE X

4-Ethoxy-3-(8-cyclopentyl-6-methyl-4-oxo-3,4-dihydro-imidazol[1,5-a][1,3,5]-triazin-2-yl)-benzenesulfonylchloride

372.3 mg (1.1 mmol) of8-cyclopentyl-2-(2-ethoxy-phenyl)-6-methyl-3H-imidazo[1,5-a][1,3,5]triazin-4-one(example IX) are added in portions to 0.66 ml (9.9 mmol) of ice-cooledchlorosulfonic acid. The mixture is subsequently stirred overnight atroom temperature before being diluted with dichloromethane and pouredonto ice water. The organic phase is separated off. The aqueous phase isextracted once again with dichloromethane and the organic phases arecombined, dried and evaporated.

Yield 266.5 mg (55.5% of theory) ¹H-NMR (200 MHz, CDCl₃): δ=1.69 (t, 3H); 1.70–2.14 (m, 8 H); 3.49–3.51 (m, 1 H); 4.45 (q, 2 H); 7.24 (d, 1H);8.11 (s, 1 H); 9.04 (d, 1 H); 9.89 (bs, 1 H).

Preparing the Active Compounds

EXAMPLE 1

2-{2-Ethoxy-5-[4-(2-hydroxy-ethyl)-piperazine-1-sulfonyl]-phenyl}-6-methyl-8-propyl-3H-imidazo[1,5-a][1,3,5]triazin-4-one

86 mg (0.66 mmol) of hydroxylethylpiperazine are added to a solution of90 mg (0.22 mmol) of4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzenesulfonylchloride (example VI) in 5 ml of dichloromethane and the reactionmixture is stirred at room temperature for 16 hours. Afterchromatographic purification (dichloromethane/methanol=95:5), 63 mg(57%) of2-{2-ethoxy-5-[4-(2-hydroxy-ethyl)-piperazine-1-sulfonyl]-phenyl}-6-methyl-8-propyl-3H-imidazo[1,5-a][1,3,5]triazin-4-oneare obtained.

400 MHz ¹H-NMR (CDCl₃): 1.00, t, 3H; 1.65, t, 3H; 1.79, hex, 2H; 1.90,s, broad, 1H; 2.56, t, 2H; 2.63, m, 4H; 2.80, t, 2H; 2.87, s, 3H, 3.09,s, broad, 4H; 3.58, m, 2H; 4.39, q, 2H; 7.16, d, 1H; 7.82, dd, 1H; 8.70,d, 1H; 10.0, s, broad, 1H.

EXAMPLE 2

2-[2-Ethoxy-5-(4-methyl-piperazine-1-sulfonyl)-phenyl]-6-methyl-8-propyl-3H-imidazo[1,5-a][1,3,5]triazin-4-one

73 mg (0.73 mmol) of N-methylpiperazine are added to a solution of 100mg (0.24 mmol) of4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzenesulfonylchloride (example VI) in 5 ml of dichloromethane and the reactionmixture is stirred at room temperature for 2 hours. Afterchromatographic purification (dichloromethane/methanol=95:5), 110 mg(95%) of2-[2-ethoxy-5-(4-methyl-piperazine-1-sulfonyl)-phenyl]-6-methyl-8-propyl-3H-imidazo[1,5-a][1,3,5]triazin-4-oneare obtained.

200 MHz ¹H-NMR (CDCl₃): 1.00, t, 3H; 1.65, t, 3H; 1.79, hex, 2H; 2.29,s, 3H; 2.50, m, 4H; 2.80, t, 2H; 2.89, s, 3H; 3.10, m, 4H; 4.37, q, 2H;7.13, d, 1H; 7.83, dd, 1H; 8.71, dd, 1H; 10.0, s, broad, 1H.

EXAMPLE 3

2-[2-Ethoxy-5-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-6-methyl-8-propyl-3H-imidazo[1,5-a][1,3,5]triazin-4-one

83 mg (0.73 mmol) of N-ethylpiperazine are added to a solution of 100 mg(0.24 mmol) of4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a]-[1,3,5]triazin-2-yl)-benzenesulfonylchloride (example VI) in 5 ml of dichloromethane and the reactionmixture is stirred at room temperature for 2 hours. Afterchromatographic purification (dichloromethane/methanol=95:5), 104 mg(87%) of2-[2-ethoxy-5-(4-ethyl-piperazine-1-sulfonyl)-phenyl]-6-methyl-8-propyl-3H-imidazo[1,5-a][1,3,5]triazin-4-oneare obtained.

200 MHz ¹H-NMR (CDCl₃): 1.00, t, 3H; 1.05, t, 3H; 1.65, t, 3H; 1.79,hex, 2H; 2.42, q, 2H; 2.54, m, 4H; 2.78, t, 2H; 2.87, s, 3H; 3.09, m,4H; 4.37, q, 2H; 7.13, d, 1H; 7.83, dd, 1H; 8.71, dd, 1H; 10.0, s,broad, 1H.

EXAMPLE 4

N-[2-(3,4-Dimethoxy-phenyl)-ethyl]-4-ethoxy-N-methyl-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzenesulfonamide

143 mg (0.73 mmol) of N-(3,4-dimethoxyphenylethyl)-N-methylamine areadded to a solution of 100 mg (0.24 mmol) of4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzenesulfonylchloride (example VI) in 5 ml of dichloromethane and the reactionmixture is stirred at room temperature for 2 hours. Afterchromatographic purification (dichloromethane/methanol=95:5), 138 mg(98%) ofN-[2-(3,4-dimethoxy-phenyl)-ethyl]-4-ethoxy-N-methyl-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzene-sulfonamideare obtained.

200 MHz ¹H-NMR (CDCl₃): 0.95, t, 3H; 1.62, t, 3H; 1.78, hex, 2H, 2.83,m, 10H; 3.31, t, 2H; 3.85, s, 6H; 4.35, q, 2H; 6.72, m, 3H; 7.09, d, 1H;7.81, dd, 1H; 8.73, d, 1H; 10.0, s, broad, 1H.

EXAMPLE 5

4-Ethoxy-N-(2-methoxy-ethyl)-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzenesulfonamide

55 mg (0.73 mmol) of 2-methoxyethylamine are added to a solution of 100mg (0.24 mmol) of4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzenesulfonylchloride (example VI) in 5 ml of dichloromethane and the reactionmixture is stirred at room temperature for 2 hours. Afterchromatographic purification (dichloromethane/methanol=95:5) andstirring up with diethyl ether, 64 mg (57%) of4-ethoxy-N-(2-methoxy-ethyl)-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzenesulfonamideare obtained.

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H; 1.65, t, 3H; 1.80, hex, 2H, 2.80,t, 2H; 2.88, s, 3H, 3.18, t, 2H; 3.30, s, 3H; 3.46, t, 2H; 4.38, q, 2H,7.13, d, 1H, 7.95, dd, 1H, 8.85, d, 1H, 10.02, s, broad, 1H.

EXAMPLE 6

2-[2-Ethoxy-5-(4-hydroxyl-piperidine-1-sulfonyl)-phenyl]-6-methyl-8-propyl-3H-imidazo[1,5-a][1,3,5]triazin-4-one

74 mg (0.73 mmol) of 4-hydroxylpiperidine are added to a solution of 100mg (0.24 mmol) of4-ethoxy-3-(6-methyl-4-oxo-8-propyl-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzenesulfonylchloride (example VI) in 5 ml of dichloromethane and the reactionmixture is stirred at room temperature for 2 hours. Afterchromatographic purification (dichloromethane/methanol=95:5), 100 mg(87%) of2-[2-ethoxy-5-(4-hydroxyl-piperidine-1-sulfonyl)-phenyl]-6-methyl-8-propyl-3H-imidazo[1,5-a][1,3,5]triazin-4-oneare obtained.

200 MHz ¹H-NMR (CDCl₃): 1.01, t, 3H; 1.65, m, 9H; 2H, 2.78, t, 2H; 2.88,s, 3H; 3.00, m 2H; 3.30, m, 2H; 3.83, s, 1H; 4.38, q, 2H, 7.15, d, 1H,7.85, dd, 1H, 8.73, d, 1H, 10.02, s, broad, 1H.

EXAMPLE 7

N-(N-Hydroxyethyl-piperazinyl)-[4-ethoxy-3-(8-cyclopentyl-6-methyl-4-oxo-3,4-dihydro-imidazol[1,5-a][1,3,5]triazin-2-yl]-benzenesulfonamide

130 mg (0.3 mmol) of4-ethoxy-3-(8-cyclopentyl-6-methyl-4-oxo-3,4-dihydro-imidazol[1,5-a][1,3,5]triazin-2-yl)-benzenesulfonylchloride (example X) are initially introduced in 7 ml ofdichloromethane. 116.2 mg (0.89 mmol) of N-hydroxyethylpiperazine areadded and the mixture is subsequently stirred overnight at roomtemperature. Purification is effected by flash chromatography using a)cyclohexane/ethyl acetate 1:1 and b) dichloromethane/methanol 95:5.

Yield: 151.4 mg (94.3% of theory) R_(f) value=0.477,dichloromethane/methanol 95:5MS (DCI, NH₃): m/z (%)=531 (M+H) (100)¹H-NMR (200 MHz, CDCl₃ ): δ=1.64 (t, 3H); 1.67–2.08 (m, 8 H); 2.35 (bs,1 H); 2.55–2.69 (m, 6H); 2.87 (s, 3 H); 3.08–3.13 (m, 4 H); 3.40 (qui, 1H); 3.59 (bt, 2 H); 4.38 (q, 2 H); 7.18 (d, 1 H); 7.83 (dd, 1 H); 8.71(d, 1 H); 9.97 (bs, 1 H).

EXAMPLE 8

N-[2-(3,4-Dimethoxy-phenyl)-ethyl-methyl]-4-ethoxy-5-[8-cyclopentyl-6-methyl-4-oxo-3,4-dihydro-imidazo[1,5-a][1,3,5]triazin-2-yl)-benzenesulfonamide

130 mg (0.3 mmol) of4-ethoxy-3-(8-cyclopentyl-6-methyl-4-oxo-3,4-dihydro-imidazol[1,5-a][1,3,5]triazin-2-yl)-benzenesulfonylchloride (example X) are initially introduced in 7 ml ofdichloromethane. 174.3 mg (0.89 mmol) of N-methylhomoveratrylamine areadded and the mixture is subsequently stirred overnight at roomtemperature. Purification is effected by means of flash chromatographyusing cyclohexane/ethyl acetate 1:1.

Yield: 144.5 g (81.5% of theory) R_(f) value=0.658,dichloromethane/methanol 95:5MS (DCI, NH₃): m/z (%)=596 (M+H) (100)

¹H-NMR (200 MHz, CDCl₃): δ=1.65 (t, 3 H); 1.72–2.08 (m, 8 H); 2.80–2.91(m, 8 H); 3.27–3.41 (m, 3 H); 3.88 (s, 6 H); 4.36 (q, 2 H); 6.70–6.81(m, 3 H); 7.10 (d, 1 H); 7.81 (dd, 1 H); 8.74 (d, 1 H); 9.98 (bs, 1 H).

The sulfonamides which are listed in the following tables 1 and 2 wereprepared by means of automated parallel synthesis from the sulfonylchlorides example VI (table 1) and example X (table 2), respectively,and the corresponding amines using one of the three following standardprotocols.

The purity of the end products was determined by means of HPLC whilethey were characterized by means of LC-MS measurement. The numericalvalue specified in the % (HPLC) column indicates the content of the endproduct which is characterized by the molar peak. Standard protocol Awas used in the case of amines possessing acid functionalies, standardprotocol B in the case of amines possessing neutral functionalities, andstandard protocol C in the case of amines possessing additional basicfunctionalities.

In the case of compounds which are listed in the following tables 1 and2 and which optically exhibit a free nitrogen valency, this latter is tobe understood, in principle, as being an —NH radical.

Standard protocol A: Conversion of amines possessing acidfunctionalities 0.05 mmol of amine, 0.042 mmol of sulfonyl chloride and0.10 mmol of Na₂CO₃ are introduced initially, and 0.5 ml of a mixtureconsisting of THF/H₂O is pipetted in by hand. After 24 h at RT, 0.5 mlof a 1 M H₂SO₄ solution is added and the mixture is filtered through atwo-phase cartridge (500 mg of Extrelut (upper phase) and 500 mg ofSiO₂, mobile phase ethyl acetate). The product is obtained afterconcentrating the filtrate in vacuo.

Standard protocol B: Conversion of amines possessing neutralfunctionalities 0.125 mmol of amine is introduced initially and 0.03mmol of sulfonyl chloride, as a solution in 1,2-dichloroethane, ispipetted in by the synthesizer. After 24 h, 0.5 ml of 1 M H₂SO₄ is addedto the mixture and the latter is filtered through a two-phase cartridge(500 mg of Extrelut (upper phase) and 500 mg of SiO₂, mobile phase:ethylacetate). The filtrate is concentrated in vacuo.

Standard protocol C: Conversion of amines possessing basicfunctionalities 0.05 mmol of amine is introduced initially and 0.038mmol of sulfonyl chloride, as a solution in 1,2-dichloroethane, and 0.05mmol of triethylamine, as a solution in 1,2-dichloroethane, are pipettedin by the synthesizer. After 24 h, 3 ml of saturated NaHCO₃ solution areadded initially and the reaction mixture is then filtered through atwo-phase cartridge. The product is obtained after the filtrate has beenconcentrated in vacuo.

All the reactions are monitored by thin layer chromatography. If thereaction has not been completed after 24 hours at RT, the mixture isthen heated at 60° C. for a further 12 hours and the experiment issubsequently terminated.

TABLE 1 HPLC- Ex . MW Area % at no. Structure [g/mol] 210 nm Mz + H 9

555.66 82 556 10

511.60 78 512 11

477.59 88 478 12

477.59 88 478 13

477.59 85 478 14

511.60 61 512 15

477.59 81 478 16

617.67 89 618 17

407.45 54 408 18

463.56 71 464 19

503.63 89 504 20

538.63 89 539 21

544.63 91 545 22

525.63 84 526 23

525.63 92 526 24

502.60 72 503 25

511.60 91 512 26

643.77 83 644 27

491.61 94 492 28

539.66 77 540 29

447.56 97 448 30

599.71 89 600 31

535.67 96 536 32

521.64 75 522

TABLE 2 Ex. MW HPLC % Mz + no. Structure [g/mol] (210 nm) H 33

503.63 76 504 34

503.63 86 504 35

503.63 75 504 36

489.60 80 490 37

489.60 76 490 38

475.57 92 476 39

517.65 76 518 40

523.62 79 524 41

537.64 71 538 42

600.72 75 601 43

535.65 72 536 44

536.66 65 537 45

537.64 83 538 46

607.73 69 608 47

523.62 84 524 48

553.64 82 544 49

537.64 74 538 50

523.62 88 524 51

583.67 89 584 52

544.68 78 545 53

537.64 78 538 54

475.57 83 476 55

447.52 86 448 56

528.63 70 529 57

503.63 91 504 58

503.63 75 504 59

550.68 88 551 60

537.64 78 538 61

530.65 75 531 62

475.57 81 476 63

501.61 94 502

1. A method for treatment of cardiovascular diseases comprisingadministering to a mammal in need thereof an effective amount of acompound of Formula (I)

in which R¹ represents straight-chain or branched alkyl having up to 4carbon atoms, R² represents straight-chain or branched alkyl having upto 4 carbon atoms or represents cyclopentyl, R³ represents hydrogen orstraight-chain or branched alkyl having up to 4 carbon atoms, R⁴ and R⁵are identical or different and represent hydrogen, (C₁–C₆)-alkoxy orhydroxyl or represent (C₁–C₈)-alkyl which is optionally substituted, upto 3 times, identically or differently, by hydroxyl or (C₁–C₆)-alkoxy orby radicals of the formulae

in which R⁶ and R⁷ are identical or different and denote hydrogen or(C₁–C₆)-alkyl, and/or, for its part, (C₁–C₈)-alkyl is optionallysubstituted by phenyl or phenoxy which, for their part, are optionallysubstituted, once to three times, identically or differently, byhalogen, hydroxyl, (C₁–C₆)-alkoxy or (C₁–C₆)-alkyl or by a radical ofthe formula —SO₂NR⁸R^(9,) in which R⁸ and R⁹ are identical or differentand denote hydrogen or (C₁–C₆)-alkyl, or R⁴ represents hydrogen ormethyl, and R⁵ represents radicals of the formulae

or represents phenyl which is optionally substituted, up to 3 times,identically or differently, by halogen, acetyl or (C₁–C₆)-alkoxy or byradicals of the formulae

—NR¹⁰R¹¹ or —CH₂—P(O)(OR¹²)(OR³), in which R¹⁰ and R¹¹ are identical ordifferent and denote hydrogen or (C₁–C₄)-alkyl, R¹² and R¹³ areidentical or different and denote hydrogen or (C₁–C₆)-alkyl, or R⁴ andR^(5,) together with the nitrogen atom to which they are bonded, formradicals of the formulae

in which R¹⁴ and R¹⁵ are identical or different and denote hydroxyl,hydrogen or (C₁–C₄)-alkyl which is optionally substituted by hydroxyl,or R¹⁴ denotes hydrogen, and R¹⁵ denotes a radical of the formula

or R¹⁴ and R¹⁵ together form a radical of the formula ═N—O—CH_(3,) R¹⁶denotes hydrogen or (C1–C8)-alkyl which is optionally substituted byhydroxyl, or a 5- to 6-membered, aromatic heterocycle having up to 3heteroatoms from the series S, N and/or O, or the salts, N-oxides andisomeric forms thereof.
 2. The method of claim 1 wherein saidcardiovascular diseases are selected from high blood pressure, neuronalhypertension, stable and unstable angina, arrhythmias, thromboembolicdiseases and ischemias, myocardial infarction, stroke, transitory andischemic attacks, angina pectoris, percutaneous transluminal angioplasty(PTA), percutaneous transluminal coronary angioplasties (PTCA) andbypass.
 3. The method of claim 1, wherein said compound is administeredintravenously or orally.